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Article

Summary

Concerns about the safety of whole-cell pertussis vaccines
prompted development of acellular vaccines that are less likely
to provoke adverse events because they contain purified antigenic
components of Bordetella pertussis. Two diphtheria and tetanus
toxoids and acellular pertussis (DTaP) vaccines -- ACEL-IMUNE{Registered} *
and Tripedia{Registered} ** -- have been licensed for several years, but
(until recently) only for administration of the fourth and fifth doses
in the series to children aged 15 months-6 years who previously had
received three or more doses of diphtheria and tetanus toxoids and
whole-cell pertussis (DTP) vaccine. Published reports indicate that, when
administered to infants aged 2, 4, and 6 months, acellular
pertussis vaccines are effective in preventing pertussis disease
and associated with fewer local, systemic, and certain more
serious adverse events than whole-cell pertussis vaccines. On the
basis of these data, the Food and Drug Administration (FDA) has
licensed three DTaP vaccines for use among children aged 6 weeks-6 years.
Tripedia{Registered} is now licensed for the initial
four doses, and ACEL-IMUNE{Registered} for all five doses of the
diphtheria, tetanus and pertussis vaccination series. A third
DTaP vaccine (Infanrix TM) *** was licensed in January 1997 for the
initial four doses of the series. Tripedia{Registered},
ACEL-IMUNE{Registered}, and Infanrix TM are now recommended for
routine vaccination of infants and young children, although
whole-cell pertussis vaccines remain acceptable alternatives.
Tripedia{Registered}, ACEL-IMUNE{Registered}, and Infanrix TM are
recommended for all remaining doses in the schedule for children
who have started the vaccination series with one, two, three, or
four doses of whole-cell pertussis vaccines. In September 1996,
FDA licensed the use of TriHIBit TM (ActHIB{Registered}
reconstituted with Tripedia{Registered}) **** for the fourth dose
in the series of vaccinations against diphtheria, tetanus,
pertussis, and Haemophilus influenzae type b disease.

This statement a) provides general information regarding
whole-cell pertussis vaccines currently licensed in the United
States; b) summarizes results of recent studies of the
immunogenicity, efficacy, and safety of acellular pertussis
vaccines administered to infants and young children; c) presents
recommendations for the use of Tripedia{Registered}, TriHIBit TM,
ACEL-IMUNE{Registered}, and Infanrix TM vaccines; and d)
supplements previous recommendations on pertussis vaccination.

INTRODUCTION
Whole-Cell Pertussis Vaccines

Four diphtheria and tetanus toxoids combined with whole-cell
pertussis (DTP) vaccines are presently licensed for use in the
United States.@ Vaccines of this type, prepared from suspensions
of inactivated Bordetella pertussis bacterial cells, have been
licensed for routine vaccination of infants since the mid-1940s.
Based on controlled efficacy trials conducted in the 1940s and on
subsequent observational efficacy studies, a primary series
comprising four doses of whole-cell DTP vaccine is considered
70%-90% effective in preventing serious pertussis disease (1-4).

Whole-cell DTP vaccines are commonly associated with several
local adverse events (e.g., erythema, swelling, and pain at the
injection site), fever, and other mild systemic events (e.g.,
drowsiness, fretfulness, and anorexia) (5,6). More severe
systemic events (e.g., convulsions {with or without fever} and
hypotonic hyporesponsive episodes) occur less frequently (ratio
of one case to 1,750 doses administered) among children who
receive whole-cell DTP vaccine (5). Acute encephalopathy occurs
even more rarely (ratio of 0-10.5 cases to one million doses
administered) (7). Experts disagree on whether whole-cell
pertussis vaccine causes lasting brain damage, but agree that if
the vaccine causes such damage it does so only rarely (7).
Concerns about safety prompted the development of more purified
(acellular) pertussis vaccines that are associated with a lower
frequency of adverse events and are effective in preventing
pertussis disease.

Trends in Pertussis Disease in the United States

In the United States, the highest recorded annual incidence
of pertussis occurred in 1934 when greater than 260,000 cases
were reported. The incidence of reported pertussis disease
declined substantially as use of whole-cell DTP vaccines became
widespread. By 1970, the reported incidence had declined greater
than 99%; the fewest cases (1,010) were reported in 1976.
However, since the early 1980s reported pertussis incidence has
increased steadily. Cyclical peaks in incidence occurred in 1983,
1986, 1990, and in 1993 when 6,586 cases were reported -- more than
in any year since 1976 (8). The number of reported cases has
increased in all age groups, but the increase is greatest among
persons aged greater than or equal to 5 years (9). Nevertheless,
infants and young children continue to have the highest risk for
pertussis and its complications (4,8,10).

The increase in reported pertussis cases has occurred
despite pertussis vaccination coverage levels that are higher
than at any time in the past. The proportion of children aged 19-35
months who had received three or more doses of whole-cell DTP
or diphtheria and tetanus toxoids vaccine (DT) reached 93% in
1994 (11). (Of those vaccinated, less than 2% are estimated to
have received DT {CDC, unpublished data}.) Possible explanations
of this increase in disease include a) decreased vaccine
efficacy, b) waning immunity among adolescents and adults
vaccinated during childhood, c) increased diagnosis and reporting
of pertussis because of greater awareness among physicians about
the disease, and d) enhanced surveillance and more complete
reporting in some states (12,13).

Recent randomized controlled trials in Sweden and in Italy
with one of the whole-cell DTP vaccines presently licensed in the
United States (manufactured by Connaught Laboratories, Inc.)
yielded estimates of low clinical efficacy -- 60% in the 6 months
immediately following administration of the third dose. Estimates
of vaccine efficacy for the total followup period were even
lower -- 48% in Sweden and 36% in Italy (14,15). These estimates
were substantially lower than expected on the basis of estimates
obtained from observational studies in the United States. One
possible explanation for the disparity is the number of doses
administered -- three in the trials in Sweden and Italy versus five
in the United States (doses at ages 2, 4, 6, and 12-18 months and
4-6 years). A recent study in Germany with another whole-cell DTP
vaccine currently in use in the United States (distributed by
Wyeth-Lederle Vaccines and Pediatrics) demonstrated 83%
protective efficacy after the third dose and before
administration of the fourth dose and 94% efficacy after four
doses (Wyeth-Lederle Vaccines and Pediatrics,
ACEL-IMUNE{Registered} package insert). The effectiveness of the
current pertussis vaccination program in the United States, which
has relied on four different whole-cell DTP vaccines for primary
vaccination, remains high (3,4).

Since 1991, two acellular pertussis vaccines
(Tripedia{Registered} and ACEL-IMUNE{Registered}) have been
licensed for use in the United States. Until recently, both
vaccines were licensed for use only as the fourth and fifth doses
of the diphtheria, tetanus, and pertussis vaccination series
among children aged 15 months-6 years who had received three
primary doses of whole-cell DTP (16,17). This licensure was based
on findings of studies conducted in Sweden and Japan. These
studies did not evaluate the efficacy of acellular pertussis
vaccines administered to infants on a schedule similar to the one
used in the United States and did not directly compare the
efficacy of DTaP vaccines with that of whole-cell DTP vaccines
(18-22).

Studies of the Efficacy of DTaP Vaccines in Infants

Since 1991, seven studies conducted in Europe and Africa
have evaluated the efficacy of eight DTaP vaccines administered
to infants. The vaccines, produced by different manufacturers,
contained a varying number and quantity of antigens. The
derivation and formulation of the individual antigens also varied
among vaccines (Table 1). Four doses of vaccine were administered
in one study (Wyeth-Lederle Vaccines and Pediatrics,
ACEL-IMUNE{Registered} package insert); the other six studies
involved three doses (14,15,23-25). These studies also differed
in other ways (Table 2):

Design. Three studies were randomized placebo-controlled
clinical trials; such studies usually provide the most accurate
measure of a treatment effect and are less subject to biases than
observational studies.

Because of these differences, comparisons among studies
should be made with caution. Within individual studies, however,
the efficacy of acellular pertussis vaccines can be compared
directly with that of whole-cell DTP.

The efficacy of three doses of acellular pertussis vaccines
in preventing moderate to severe pertussis disease was within the
range expected for most whole-cell DTP vaccines. Point estimates
of efficacy ranged from 59% to 89%. Mild local and systemic
adverse events occurred less frequently among infants vaccinated
with acellular pertussis vaccines for the first three or four
doses than among those vaccinated with whole-cell DTP. More
serious adverse events (e.g., fever greater than or equal to 105
F {greater than or equal to 40.5 C}, persistent crying of greater
than or equal to 3 hours duration, hypotonic hyporesponsive
episodes, and seizures) generally occurred less frequently among
infants who received acellular pertussis vaccines than among
those vaccinated with whole-cell DTP. The number of subjects
included in these studies was insufficient to estimate the risk
for rare severe reactions (i.e., encephalopathy or anaphylactic
shock). Surveillance for these rare adverse events will be needed
as acellular pertussis vaccines are used more widely.

Interpretation of Immunogenicity Data

The findings of efficacy studies have not demonstrated a
direct correlation between antibody responses and protection
against pertussis disease. However, antibody studies are useful
to compare immune responses elicited by a single vaccine under
different conditions or in different studies. Thus, efficacy
studies are required to measure clinical protection conferred by
each pertussis vaccine.

TRIPEDIA{Registered}

On July 31, 1996, the Food and Drug Administration (FDA)
licensed Tripedia{Registered} for use as the initial four doses
of the recommended diphtheria, tetanus, and pertussis vaccination
series among children aged 6 weeks-6 years. The acellular
pertussis vaccine components are purified from B. pertussis by
salt precipitation, ultracentrifugation, and ultrafiltration.
After purification, fractions containing PT and FHA are combined
to obtain a 1:1 ratio and are treated with formaldehyde to
inactivate PT. Each dose of Tripedia{Registered} contains
approximately 23.4 ug protein of inactivated PT (toxoid) and 23.4
ug protein of FHA, as well as 6.7 limit of flocculation units
(Lf) of diphtheria toxoid and 5.0 Lf of tetanus toxoid. The
combined components are adsorbed using aluminum potassium sulfate
and preserved with 1:10,000 thimerosal (Table 1).

Immunogenicity

The Multicenter Acellular Pertussis Trial, an immunogenicity
and safety study conducted in six centers in the United States
and sponsored by the National Institutes of Health (NIH),
compared antibody responses of infants vaccinated at ages 2, 4,
and 6 months with whole-cell DTP or with one of 13 different
acellular pertussis vaccines, including Tripedia{Registered}.
Antibody to pertussis antigens was measured in serum samples
taken before administration of the first dose and 1 month after
administration of the third dose of Tripedia{Registered}; 99% and
86% of children had fourfold or greater increases in titers of
antibody to PT and FHA, respectively. More than 90% of children
administered Tripedia{Registered} developed diphtheria and
tetanus antibody levels indicative of immunity to these diseases
(i.e., greater than 0.1 antitoxin units {u} per mL and greater
than 0.01 u/mL, respectively), as did greater than or equal to
90% of those administered whole-cell DTP (26). The immunogenicity
of Tripedia{Registered} when administered as a fourth dose to
children aged 12-14 months has not been studied.

Clinical Efficacy

Two studies conducted in Sweden and Germany provide data
concerning the clinical efficacy of Tripedia{Registered}. During
1985-1987, a randomized, placebo-controlled clinical trial in
Sweden examined the efficacy of two doses of two acellular
pertussis vaccines. The acellular pertussis component of one
vaccine was comparable to the acellular pertussis component of
Tripedia{Registered} (17,18). The first dose was administered at
age 5-11 months, the second dose 8-12 weeks later. For
culture-confirmed disease with cough of any duration, the
vaccine's efficacy after two doses was 69% (95% confidence
interval {CI}=47%-82%) (18). Using a more stringent case
definition (i.e., greater than or equal to 21 days paroxysmal
cough and confirmation by culture) resulted in an efficacy
estimate of 81% (95% CI=61%-90%) (27). A non-blinded follow-up
study conducted during the 42-month period following the clinical
trial yielded similar results (28).

A case-control study in Germany evaluated the efficacy of
three doses of Tripedia{Registered} administered to children aged
approximately 3, 5, and 7 months (Connaught Laboratories,
Inc.,Tripedia{Registered} package insert). Comparison groups
received whole-cell DTP (manufactured by Behringwerke, A.G.), DT,
or no vaccine. A case of pertussis was defined as an illness with
cough of greater than or equal to 21 days duration and
confirmation by positive culture for B. pertussis or household
contact with a culture-proven case. The estimated clinical
efficacy of three doses of Tripedia{Registered} compared with DT
was 80% (95% CI=59%-90%). For infants who received three doses of
whole-cell DTP, the vaccine efficacy estimate was 95% (95%
CI=81%-99%) (25). However, the two efficacy estimates are not
directly comparable because of differences in the way infants
were enrolled in the two groups.

Safety

The safety of Tripedia{Registered} was assessed in studies
conducted in the United States and Germany. Local reactions
(e.g., erythema, swelling, or pain), fever, and other common
systemic symptoms (e.g., anorexia, vomiting, drowsiness, or
fussiness) occurred less frequently among infants administered
Tripedia{Registered} than among those who received whole-cell DTP
(Connaught Laboratories, Inc., Tripedia{Registered} package
insert). In the Multicenter Acellular Pertussis Trial, local and
common systemic events occurred less frequently among
Tripedia{Registered} recipients than among recipients of
whole-cell DTP (Table 3) (29). Among recipients of 41,615 doses
of Tripedia{Registered} in the trial in Germany, few moderate to
severe adverse events occurred within 7 days after vaccination
(Connaught Laboratories, Inc., Tripedia{Registered} package
insert). The following events and rates of occurrence (per 1,000
doses administered) were reported: persistent crying for greater
than or equal to 3 hours, 0.12; febrile seizures, 0.05; afebrile
seizures, 0.02; and hypotonic hyporesponsive episodes, 0.05.
Rates of invasive bacterial infections, hospitalizations, and
deaths among infants vaccinated with Tripedia{Registered} were
similar to those observed among recipients of DT. None of the
deaths or invasive bacterial infections was vaccine related.

In a study conducted in the United States, children aged 15-20
months who had received Tripedia{Registered} (n=109) or whole-cell DTP
(n=30) for the first three doses were administered Tripedia{Registered}
as the fourth dose (30). Although the differences were not statistically
significant, the percentages of children who had local adverse events
(e.g., erythema, swelling, or pain) or certain systemic adverse events
(i.e., temperature greater than 101 F {greater than 38.3 C} or
irritability) within 72 hours after administration of the fourth
dose was higher among children who had received Tripedia{Registered} for
the first three doses. However, the frequency of adverse events was lower
than that observed in previous studies in which a fourth dose of
whole-cell DTP followed three previous doses of whole-cell DTP.

Limited data are available to evaluate the safety of
Tripedia{Registered} when administered as a fifth dose to
children aged 4-6 years who have received four previous doses of
Tripedia{Registered}. The frequency of local and mild systemic
reactions after the last of five doses was no greater among
children administered Tripedia{Registered} (n=18) than among
children in the same study who were administered five doses of
whole-cell DTP (n=10) (M.E. Pichichero, unpublished data). More
data concerning the safety of Tripedia{Registered} in such
circumstances are being collected and will be available before
infants who receive Tripedia{Registered} for the first four doses
require a fifth dose at age 4-6 years. Data are insufficient to
assess the safety of Tripedia{Registered} administered to persons
aged greater than or equal to 7 years.

Simultaneous Administration

Data concerning the immunogenicity of Tripedia{Registered}
administered simultaneously with other childhood vaccines are
limited. In a clinical study, infants received
Tripedia{Registered}, Haemophilus influenzae type b (Hib)
conjugate vaccine (tetanus toxoid conjugate)
(ActHIB{Registered}), oral poliovirus vaccine (OPV), and
hepatitis B vaccine simultaneously (Connaught Laboratories, Inc.,
Tripedia{Registered} package insert). In one of the study groups,
infants were administered Tripedia{Registered},
ActHIB{Registered}, and OPV at ages 2, 4, and 6 months, and
hepatitis B vaccine at ages 2 and 4 months. After three doses,
all of the 69 children who received ActHIB{Registered}
simultaneously with Tripedia{Registered} vaccine had serum Hib
capsular polysaccharide antibody (anti-PRP) levels indicative of
clinical protection (greater than or equal to 1 ug/mL). Testing
of sera from a group of 12 infants administered hepatitis B
vaccine simultaneously with the other two vaccines at ages 2 and
4 months documented a protective antibody response in 11 of the
infants (93%) (i.e., anti-hepatitis B surface antigen {anti-HBs}
levels of greater than 10 mIU/mL). Testing of sera from another
subset of 20 infants who were administered OPV simultaneously
with the other vaccines at ages 2, 4, and 6 months demonstrated
that 100% had protective neutralizing antibody to all three
poliovirus types. Children (n=9) to whom Tripedia{Registered},
ActHIB{Registered}, and measles, mumps, and rubella (MMR) vaccine
were administered simultaneously at separate sites developed
antibody to measles, mumps, and rubella. Simultaneous
administration of Tripedia{Registered} and inactivated poliovirus
vaccine (IPV) or varicella vaccine has not been studied.

TRIHIBIT TM

On September 27, 1996, FDA licensed TriHIBit TM
(ActHIB{Registered} vaccine reconstituted with
Tripedia{Registered} vaccine) for the fourth doses of the
diptheria, tetanus, and pertusssis vaccine series and the Hib
vaccine series. When ActHIB{Registered} is combined with
Tripedia{Registered} by reconstitution, each dose contains 10 ug
of purified Hib capsular polysaccharide conjugated to 24 ug of
inactivated tetanus toxoid and 8.5% of sucrose, in addition to
the content of Tripedia{Registered}.

Immunogenicity

In a randomized clinical trial, children aged 15-20 months
were administered either Tripedia{Registered} and
ActHIB{Registered} vaccines at separate sites (n=98) or combined
as a single dose (n=93) (Connaught Laboratories, Inc.,
Tripedia{Registered} package insert). Before the study began,
these children all had received three doses of a Hib conjugate
vaccine and three doses of whole-cell DTP at approximately ages
2, 4, and 6 months. One month after administration of the fourth
dose, 100% of the children in both groups had anti-PRP antibody
concentrations greater than or equal to 1 ug/mL, an indication of
long-term protection against invasive H. influenzae type b
disease. The proportions of children with protective antibody
responses to diphtheria and tetanus toxoids were also high and
similar in the two groups. The proportions of children who had
fourfold or greater serum antibody responses to PT (measured by
enzyme-linked immunosorbent assay {ELISA} or Chinese hamster
ovary {CHO} cell assay) were greater than 85% in both groups.
Among children who received TriHIBit TM, the proportion with
fourfold or greater antibody responses to FHA was slightly lower.
The clinical importance of this difference is not known.

Clinical Efficacy

TriHIBit TM has been licensed for use as the fourth dose of
the two vaccination series on the basis of immunogenicity and
safety data. Its protective efficacy when used for this purpose
has not been evaluated.

Safety

The safety of TriHIBit TM was evaluated in two studies
involving a total of 960 children who had each received three
doses of a Hib vaccine and three doses of whole-cell DTP vaccine
at approximately ages 2, 4, and 6 months (Connaught Laboratories,
Inc., Tripedia{Registered} package insert). At age 15-20 months,
these children were administered the fourth dose of
Tripedia{Registered} and ActHIB{Registered} vaccines either
combined by reconstitution as a single injection or as two
injections at separate sites. Rates of local and systemic
reactions were similar in the two groups. Local reactions were
mild and resolved within 48 hours following vaccination. The most
common local reaction was pain at the injection site.

Simultaneous Administration

When TriHIBit TM was administered to children aged 15-20
months (n=47) simultaneously with MMR vaccine, greater than 95%
developed serum antibody to measles, mumps, and rubella at levels
indicative of protection against these diseases (Connaught
Laboratories, Inc., Tripedia{Registered} package insert). Immune
responses to OPV or IPV and hepatitis B vaccine when administered
simultaneously with TriHIBit TM have not been studied.

ACEL-IMUNE{Registered}

On December 30, 1996, FDA licensed ACEL-IMUNE{Registered}
for all five doses of the recommended diphtheria, tetanus, and
pertussis vaccination series among children aged 6 weeks-6 years.
Each dose of the acellular pertussis component of
ACEL-IMUNE{Registered} contains approximately 34.4 ug of FHA, 3.2
ug of inactivated PT, 1.6 ug of Pn, and 0.8 ug of Fim type 2. The
acellular pertussis vaccine components are purified by ammonium
sulfate fractionation and sucrose density gradient
centrifugation. PT is detoxified by treatment with formaldehyde.
Each dose of ACEL-IMUNE{Registered} contains 9.0 Lf units of
diphtheria toxoid, 5.0 Lf units of tetanus toxoid, and 300
hemagglutinating units of acellular pertussis vaccine. The FHA
and PT components both exhibit hemagglutinating activity. The
combined components are adsorbed to aluminum hydroxide and
aluminum phosphate and preserved with 1:10,000 thimerosal (Table 1).

Immunogenicity

Data from the Multicenter Acellular Pertussis Trial provide
evidence of the immunogenicity of ACEL-IMUNE{Registered} (26).
Investigators measured levels of serum antibody to each of the
four vaccine antigens after administration of three doses. The
percentages of vaccinees with fourfold or greater increases in
antibody titer (compared with prevaccination levels) were: PT,
67%; FHA, 80%; Pn, 71%; and Fim, 59%. The percentages of these
children who developed diphtheria antibody levels of greater than
or equal to 0.1 u/mL and tetanus antibody levels of greater than
or equal to 0.01 u/mL (i.e., indications of immunity against
these diseases) were 86% and 100%, respectively. Antibody
responses observed among children in the United States were
similar to those observed among children in the study in Germany
that demonstrated the efficacy of ACEL-IMUNE{Registered}.

Antibody response to ACEL-IMUNE{Registered} when

administered to children aged 12-14 months was evaluated in a
clinical trial (Wyeth-Lederle Vaccines and Pediatrics,
unpublished data). ACEL-IMUNE{Registered} was administered as a
fourth dose to children aged 12-14 months (n=58) or 15-18 months
(n=50) who had previously received three doses of whole-cell DTP.
In both age groups, greater than 85% of the children had twofold
or greater antibody responses to PT, FHA, Pn, and Fim.

Clinical Efficacy

Efficacy of ACEL-IMUNE{Registered} was assessed in a
prospective study in Erlangen, Germany (Wyeth-Lederle Vaccines
and Pediatrics, ACEL-IMUNE{Registered} package insert). Infants
were randomly assigned to groups that were administered either
ACEL-IMUNE{Registered} or whole-cell DTP (distributed by
Wyeth-Lederle Vaccines and Pediatrics) at a mean age of 3, 5, 7,
and 17 months. A third group of infants (not selected randomly)
received DT at ages 3, 5, and 17 months. In this study, pertussis
was defined as cough illness lasting greater than or equal to 21
days with at least one pertussis-associated symptom (paroxysms,
whoop, or post-tussive vomiting) confirmed by culture, serology,
or epidemiologic link to a culture-positive household contact.
Between the third and fourth doses, the efficacy of
ACEL-IMUNE{Registered} (compared with DT) was 73% (95% CI=51%-86%) and
the efficacy of whole-cell DTP 83% (95% CI=65%-92%). After four doses,
the efficacy of ACEL-IMUNE{Registered} was 85% (95% CI=76%-90%), and
that of whole-cell DTP was 94% (95% CI=89%-97%). Considering the full
observation period after the third and fourth doses, the adjusted
efficacy of ACEL-IMUNE{Registered} was 81% (95% CI=73%-87%) compared
with 91% (95% CI=85%-95%) for whole-cell DTP.

Safety

Studies from the United States and Germany provide data
concerning the frequency and nature of adverse events that occur
after administration of ACEL-IMUNE{Registered}. In the
Multicenter Acellular Pertussis Trial, children who were
administered ACEL-IMUNE{Registered} experienced fewer local
adverse events (e.g., pain, redness, or swelling at the injection
site) and systemic adverse events (e.g., temperature greater than
101 F {greater than 38.3 C}, or fussiness) after any of the first
three doses than children who were administered whole-cell DTP
(Table 3) (29). Similarly, in other studies conducted in the
United States and Germany, adverse events (local and systemic)
after any of the initial four doses occurred less frequently
among children who received ACEL-IMUNE{Registered} than among
children administered whole-cell DTP (Wyeth-Lederle Vaccines and
Pediatrics, ACEL-IMUNE{Registered} package insert). Rates of
adverse events increased with the number of previous doses of
ACEL-IMUNE{Registered} administered, but were lower than rates
for children who received the same number of doses of whole-cell
DTP. Among 357 children who were administered five doses of
ACEL-IMUNE{Registered}, adverse events occurred no more
frequently than among children in previous studies (historical
controls) who received five doses of whole-cell DTP
(Wyeth-Lederle Vaccines and Pediatrics, ACEL-IMUNE{Registered}
package insert).

In the efficacy trial in Germany (n=16,642 doses of
ACEL-IMUNE{Registered}), the following rates of moderate to
severe adverse events (per 1,000 doses administered) were
observed within 72 hours after administration of the vaccine:
persistent or unusual cry, 1.14; temperature greater than or
equal to 105 F (greater than or equal to 40.5 C), 0.06; febrile
seizures (no other type of seizure occurred), 0.06; and hypotonic
hyporesponsive episodes, 0 (Wyeth-Lederle Vaccines and
Pediatrics, ACEL-IMUNE{Registered} package insert). Rates of all
these adverse events were higher among children who received
whole-cell DTP.

A clinical trial examined the frequency of local reactions
(e.g., erythema, induration, or tenderness) and systemic
reactions (e.g., fever, fussiness, drowsiness, or anorexia) among
children aged 12-14 months or 15-18 months, all of whom had
previously received three doses of whole-cell DTP. Differences in
the frequency of adverse reactions in the two age groups were not
statistically significant (Wyeth-Lederle Vaccines and Pediatrics,
unpublished data).

Neither anaphylaxis nor encephalopathy occurred during
clinical trials that involved administration of 25,899 doses of
ACEL-IMUNE{Registered}. Six deaths of infants or young children
who participated in these trials were reported to study
investigators; none was vaccine-related and all occurred greater
than 4 weeks after vaccination (Wyeth-Lederle Vaccines and
Pediatrics, ACEL-IMUNE{Registered} package insert). The
reactogenicity of ACEL-IMUNE{Registered} among persons aged
greater than or equal to 7 years has not been evaluated.

Simultaneous Administration

The immunogenicity of ACEL-IMUNE{Registered} when
administered simultaneously with other recommended childhood
vaccines was evaluated in three studies. ACEL-IMUNE{Registered},
Hib vaccine, and hepatitis B vaccine were administered
simultaneously to 77 infants at ages 2, 4, and 6 months. After
administration of the third dose, serum samples from 94% of the
infants demonstrated anti-PRP antibodies indicative of clinical
protection (greater than or equal to 1 ug/mL), and all of the
infants evaluated (n=74) had antibody levels indicative of
protection against hepatitis B (i.e., anti-HBs titers of greater
than 10 mIU/mL) (Wyeth-Lederle Vaccines and Pediatrics,
ACEL-IMUNE{Registered} package insert). In another clinical
study, 30 infants were administered OPV simultaneously with
ACEL-IMUNE{Registered} at ages 2 and 4 months; greater than or
equal to 90% had protective neutralizing antibody to all three
poliovirus types at age 6 months. When MMR vaccine was
administered simultaneously with ACEL-IMUNE{Registered} to
children aged 15-18 months (n=48), greater than or equal to 92%
developed serum antibody titers indicative of protection against
measles, mumps, and rubella. Similar results were obtained when
whole-cell DTP was administered simultaneously with OPV or MMR
vaccine (31). Simultaneous administration of
ACEL-IMUNE{Registered} and IPV or varicella vaccine has not been
evaluated.

INFANRIX TM

On January 29, 1997, FDA licensed Infanrix TM for use as the
initial four doses of the recommended diphtheria, tetanus, and
pertussis vaccination series among children aged 6 weeks-6 years.
Infanrix TM is also licensed for all remaining doses in the
schedule for children who have received one or more doses of
whole-cell DTP vaccine. Each dose of Infanrix TM contains 25 ug
PT, 25 ug FHA, 8 ug Pn, 25 Lf of diphtheria toxoid, and 10 Lf of
tetanus toxoid (Table 1). The three antigens in the acellular
pertussis vaccine component are separately purified in successive
chromatographic steps (hydrophobic, affinity, ion exchange, and
size exclusion processes). Formalin and glutaraldehyde are used
to detoxify PT; FHA and Pn are treated with formalin. The
combined components are adsorbed onto less than or equal to 0.625
mg of aluminum (as aluminum hydroxide) and preserved with
2-phenoxyethanol.

Immunogenicity

In the Multicenter Acellular Pertussis Trial, three doses of
Infanrix TM were administered to children at ages 2, 4, and 6
months. One month after the third dose, investigators measured
fourfold or greater antibody responses to PT, FHA, and Pn in
greater than or equal to 83% of children who received Infanrix TM,
a higher proportion than observed among recipients of whole-cell
DTP (26). All the children who were administered Infanrix TM
developed diphtheria antibody titers of greater than or equal to
0.1 u/mL and tetanus antibody titers of greater than or equal to
0.01 u/mL (i.e., indications of immunity against these diseases).
Whether their primary vaccination was with Infanrix TM or
whole-cell DTP, greater than 86% of children aged 15-20 months
had a fourfold or greater rise in serum antibody to each of the
pertussis antigens in the vaccine after administration of
Infanrix TM as the fourth dose (M. E. Pichichero, unpublished
data). The immunogenicity of Infanrix TM administered as a fourth
dose to children aged 12-14 months has not been studied.

Efficacy

The efficacy of Infanrix TM was evaluated in two separate
studies (Table 2). In Italy, researchers compared the efficacy of
Infanrix TM, DTaP manufactured by Chiron Biocine, whole-cell DTP
manufactured by Connaught Laboratories, and DT in a randomized
controlled trial that enrolled more than 15,000 children (15).
Participants received three doses of one of the vaccines at ages
2, 4, and 6 months. The efficacy of Infanrix TM in preventing
pertussis disease (defined as paroxysmal cough greater than or
equal to 21 days duration, with culture or serologic confirmation
of infection with B. pertussis) was 84% (95% CI=76%-89%). The
efficacy of whole-cell DTP was 36% (95% CI=14%-52%). After the
trial, children were followed in an observational study to an
average age of 33 months (range: 20-39 months); the efficacy of
Infanrix TM remained high throughout this followup period (78%,
95% CI=62%-87%) (SmithKline Beecham Pharmaceuticals, Infanrix TM
package insert).

The second study, conducted in six areas in Germany, was a
household contact study. In preparation for this study, three
doses of Infanrix TM were administered at ages 3, 4, and 5 months
to more than 22,000 infants as part of a large immunogenicity and
safety study (23). Infants who did not participate in this study
could have received whole-cell DTP vaccine (manufactured by
Behringwerke, A.G.) or DT vaccine. The efficacy study included
453 households with confirmed cases of pertussis in which 360
contact children aged 6-47 months were eligible for inclusion in
the vaccine efficacy calculations. A case of pertussis was
defined as greater than or equal to 21 days of paroxysmal cough
illness plus confirmation of B. pertussis infection by culture
and/or serologic testing. The efficacy of Infanrix TM was 89% (95%
CI=77%-95%); the efficacy of whole-cell DTP was 98% (95% CI=83%-100%).

Safety

The occurrence of adverse events following vaccination with
Infanrix TM was evaluated in clinical studies involving
approximately 30,000 children. In these studies, 28,749 infants
received Infanrix TM as a three dose primary series, 5,830
children received Infanrix TM as a fourth dose following three
doses of Infanrix TM, and 22 children received Infanrix TM as a
fifth dose following four doses of Infanrix TM. In addition, 439
children and 169 children received Infanrix TM as a fourth or
fifth dose following three or four doses of whole-cell DTP
vaccine, respectively. In comparative studies, administration of
Infanrix TM was followed by fewer of the local and systemic
adverse reactions commonly associated with whole-cell DTP
vaccination (15,29,32-34). However, results of these studies
demonstrated that the rates of erythema, swelling, and fever
increased with each successive dose of Infanrix TM (SmithKline
Beecham Pharmaceuticals, Infanrix TM package insert). In the
Multicenter Acellular Pertussis Trial, local and common systemic
adverse events occurred less frequently following any dose of
Infanrix TM in the primary series than following any dose of
whole-cell DTP (Table 3) (29).

The efficacy study conducted in Italy monitored the
frequency of moderate to severe adverse events occurring after
administration of any of the primary doses of Infanrix TM. Rates
(per 1,000 doses administered) of adverse events occurring less
than or equal to 48 hours after administration were: persistent
crying greater than or equal to 3 hours duration, 0.44; seizures,
0.07; and temperature greater than or equal to 104 F(greater than
or equal to 40.0 C), 0.36. These rates were similar to or
slightly higher than the rates reported among children who were
administered DT, but lower than those for children who received
whole-cell DTP. In this trial, no hypotonic hyporesponsive
episodes occurred among children to whom Infanrix TM was
administered.

In the safety study in Germany, data were available
regarding 1,809 children who received three doses of Infanrix TM
at ages 3, 4, and 5 months and a fourth dose at a mean age of 20
months. The percentages of children who experienced each of the
adverse events less than or equal to 3 days after administration
of the fourth dose were: redness, 46%; swelling, 35%; pain, 26%;
fever greater than or equal to 100.4 F (greater than or equal to
38 C), 26%; and restlessness, 16%. In this study the rates of
redness, swelling, pain, and fever increased with successive
doses of Infanrix TM (SmithKline Beecham Pharmaceuticals, Inc.,
Infanrix TM package insert).

Additional safety data are available from another study
conducted in Germany (SmithKline Beecham Pharmaceuticals, Inc.,
Infanrix TM package insert). Children aged 13-27 months received
Infanrix TM or whole-cell DTP (manufactured by Behringwerke, A.G.)
as a fourth dose. These children had previously received three
doses of the same vaccine. Among children administered Infanrix TM
as the fourth dose, the incidence of redness, swelling, pain,
fever, and restlessness was lower than among children
administered whole-cell DTP as the fourth dose.

Infanrix TM has not been licensed previously for
administration of the fourth or fifth dose to children who have
received three or four doses of whole-cell DTP. Two studies
conducted in the United States examined the frequency of adverse
events among children who had previously received three or four
doses of whole-cell DTP vaccine at approximately ages 2, 4, 6,
and 15-18 months (Table 4). Children aged 15-20 months received
Infanrix TM or whole-cell DTP vaccine as the fourth dose; children
aged 4-6 years were administered Infanrix TM or whole-cell DTP as
the fifth dose (33,34). Significantly fewer local and systemic
adverse events were reported following administration of
Infanrix TM than following whole-cell DTP vaccine.

In the safety study in Germany, edematous swelling of the
entire thigh into which the vaccine was injected was reported
spontaneously by parents or care-givers of 62 of 5,361 vaccinees
(1.2%) after administration of the fourth dose. The swelling
generally began within 48 hours of vaccination and resolved
spontaneously without sequelae during an average of 4 days. In
other countries where Infanrix TM has been licensed, this type
swelling has been reported rarely following administration of
Infanrix TM for any dose, including the primary series (SmithKline
Beecham Pharmaceuticals, Infanrix TM package insert). Edematous
swelling has also been reported following administration of other
DTaP vaccines, acellular pertussis vaccine alone (without DT),
whole-cell DTP vaccine and other vaccines (19,35-37). However,
the precise frequency of these reactions among vaccinated
children is unknown.

Data are insufficient to evaluate the safety of
administration of a fifth dose of Infanrix TM to children aged 4-6
years who have received Infanrix TM for the previous four doses.
Additional information regarding the immunogenicity and safety of
a fifth dose of Infanrix TM administered to children who have
received four prior doses of the same vaccine is being collected.
This information is expected to be available before infants who
receive Infanrix TM for the first four doses require a fifth dose
at age 4-6 years. The safety of Infanrix TM when administered to
persons aged greater than or equal to 7 years has not been
assessed.

Simultaneous Administration

In a clinical trial in the United States, Infanrix TM was
administered simultaneously, at separate sites, with hepatitis B
vaccine, Hib vaccine, and OPV to children aged 2, 4, and 6
months. One month after the third dose, 100% of infants (n=64)
administered hepatitis B vaccine simultaneously with Infanrix TM
demonstrated anti-HBs antibodies greater than or equal to 10
mIU/mL and 90% of infants (n=72) who received Hib vaccine
simultaneously with Infanrix TM achieved anti-PRP antibodies
greater than or equal to 1 ug/mL (i.e., antibody levels
indicative of protection against these diseases). The percentage
of infants who were administered OPV simultaneously with
Infanrix TM(n=60-61) who developed protective neutralizing
antibody to poliovirus types 1, 2, and 3 ranged from 96% to 100%
(38). No data are available regarding antibody responses to MMR
vaccine, varicella vaccine, or IPV when administered
simultaneously with Infanrix TM.

VACCINE USE

Recommended Childhood Vaccination Schedule

The routine diphtheria, tetanus, and pertussis vaccination
schedule for children aged less than 7 years comprises five doses
of vaccine containing diphtheria, tetanus, and pertussis antigens
(Table 5). Three (primary) doses should be administered during
the first year of life, generally at ages 2, 4, and 6 months. To
maintain adequate immunity during preschool years, the fourth
(first booster) dose is recommended for children aged 15-18
months. The fourth dose should be administered greater than or
equal to 6 months after the third. If the interval between the
third and fourth doses is greater than or equal to 6 months and
the child is not likely to return for a visit at the recommended
age, the fourth dose of either DTaP or whole-cell DTP may be
administered as early as age 12 months. The fifth (second
booster) dose is recommended for children aged 4-6 years to
confer continued protection against disease during the early
years of schooling. A fifth dose is not necessary if the fourth
dose in the series is administered on or after the fourth
birthday.

Vaccine Preference

DTaP vaccines are efficacious when administered to infants
as the primary series (i.e., doses 1-3). In addition, local
reactions, fever, and other systemic events occur substantially
less often after DTaP administration than after administration of
whole-cell DTP. Therefore, DTaP vaccines are recommended for all
five doses in the vaccination schedule. For children who have
started the vaccination series with one, two, three, or four
doses of whole-cell DTP, DTaP is also recommended for all
remaining doses in the schedule. During the period of transition
from use of whole-cell DTP to DTaP, whole-cell DTP is an
acceptable alternative to DTaP for any of the five doses. For the
first four doses, whole-cell DTP combined with Hib vaccine
(DTP-Hib vaccine) is an acceptable alternative to DTaP and Hib
vaccine administered at separate sites.

Licensed Products

Three acellular pertussis vaccines (Tripedia{Registered} and
Infanrix TM for the first four doses and ACEL-IMUNE{Registered}
for all five doses) are licensed for the diphtheria, tetanus, and
pertussis vaccination series. FDA has not approved
Tripedia{Registered} or Infanrix TM as the fifth dose among
persons who have received only Tripedia{Registered} or only
Infanrix TM for the first four doses in the vaccination series,
because data are insufficient to evaluate their safety in this
situation. However, such data should be available before infants
vaccinated with four doses of these vaccines require a fifth dose
at age 4-6 years.

TriHIBit TM (ActHIB{Registered} reconstituted with
Tripedia{Registered}) is licensed only for the fourth dose of the
vaccination series, and is not licensed for the first three
doses. TriHIBit TM can be used for the fourth dose following three
doses of either DTaP or whole-cell DTP and a primary series of
any Hib vaccine.

Dosage and Administration

The dose of all four vaccines -- Tripedia{Registered},
TriHIBit TM, ACEL-IMUNE{Registered}, and Infanrix TM -- is 0.5 mL,
administered intramuscularly. Fractional doses (less than 0.5 mL)
should not be administered. The preferred injection sites are the
anterolateral aspect of the thigh and the deltoid muscle of the
upper arm (39).

Whenever feasible, the same brand of DTaP vaccine should be
used for all doses of the vaccination series. Data do not exist
regarding the safety, immunogenicity, and efficacy of using DTaP
vaccines from different manufacturers for successive doses of the
primary or booster vaccination series. However, the vaccine
provider may not know or may not have available the type of DTaP
vaccine previously administered to a child. Neither circumstance
should present a barrier to administration of the vaccine and any
of the licensed DTaP vaccines may be used to complete the
vaccination series.

Simultaneous Administration of Vaccines

Limited data regarding simultaneous administration of the
first three doses of DTaP with other childhood vaccines indicate
no interference with response to any of these other antigens.
Data are available regarding administration of DTaP with the
other vaccines recommended at the same time as the fourth and
fifth doses of the diphtheria, tetanus, and pertussis series
(i.e., Hib vaccine, OPV, MMR vaccine, and varicella vaccine), and
regarding administration of whole-cell DTP (all doses in the
series) with these vaccines (40). On the basis of this
experience, DTaP may be administered simultaneously with
hepatitis B vaccine, Hib vaccine, and IPV or OPV to infants at
ages 2, 4, or 6 months as indicated in the recommended childhood
vaccination schedule (41). All vaccines appropriate to the age
and previous vaccination status of the child should be
administered simultaneously including DTaP, Hib vaccine, IPV or
OPV, hepatitis B vaccine, MMR vaccine, and varicella vaccine.

Special Considerations

Vaccination of Infants and Young Children Who Have a Personal or
Family History of Seizures

Infants and young children who have had previous seizures
(whether febrile or nonfebrile) are at greater risk for seizures
after administration of whole-cell pertussis vaccination than are
infants who do not have such a history (42). Because these
reactions may be caused by the fever induced by whole-cell DTP
and because DTaP is less frequently associated with moderate to
high fever, DTaP is the vaccine of choice when pertussis
vaccination is considered for these children.

Among infants and children with a history of previous
seizures, it is prudent to delay pertussis vaccination until the
child's neurologic status has been assessed. Infants and children
with a stable neurologic condition, including well-controlled
seizures, may be vaccinated with DTaP. Infants with evolving
neurologic conditions should not be vaccinated until a treatment
regimen has been established and the condition has stabilized.
Acetaminophen or ibuprofen may be administered to these children
at the time of DTaP vaccination and every 4 hours for 24 hours
thereafter to reduce the possibility of postvaccination fever.

Data from one study indicate that infants and young children
who have a parent or sibling with a history of convulsions are
more likely to have seizures following whole-cell DTP vaccination
than those without such histories (43). However, seizures occur
infrequently after administration of whole-cell DTP, are usually
febrile in nature, and generally have a benign outcome (44). An
estimated 5%-7% of children have parents or siblings with a
history of convulsions (43). If these children were exempted from
pertussis vaccination, unvaccinated persons and the general
population might face an increased risk for pertussis. Therefore,
a family history of convulsions or other central nervous system
disorders is not a contraindication to pertussis vaccination.
Acetaminophen or ibuprofen may be administered to these children
at the time of DTaP vaccination and every 4 hours for 24 hours
thereafter to reduce the possibility of postvaccination fever.

Children Who Have Had Pertussis Disease

Although pertussis disease is likely to confer immunity
against pertussis, the duration of such immunity is unknown.
Children with well-documented pertussis disease (i.e., positive
culture for B. pertussis or epidemiologic linkage to a
culture-positive case) should be administered DT vaccine for the
remaining doses of the vaccination series to ensure that they are
protected against diphtheria and tetanus. Some experts recommend
including the pertussis component for subsequent vaccination of
infants who have had culture-proven pertussis because infants may
have a suboptimal immune response following B. pertussis
infection (45).

Pertussis Vaccination for Persons Aged Greater than or Equal to
7 Years

Pertussis vaccines are presently licensed for use only among
children aged 6 weeks-6 years. In the United States, adolescents
and adults whose immunity has waned are an important reservoir
for B. pertussis and may infect unvaccinated young children. In
the future, booster doses of adult formulations of acellular
pertussis vaccines may be recommended to prevent the occurrence
and spread of the disease among these older persons. However,
acellular pertussis vaccines combined with diphtheria and tetanus
toxoids will need to be reformulated for use in adults because
all infant formulations contain more diphtheria toxoid than is
recommended for persons aged greater than or equal to 7 years.
Recommendations regarding routine vaccination of adults will
require additional research (e.g., studies of the incidence,
severity, and cost of pertussis among adolescents and adults;
studies of the effectiveness and safety of adult formulations of
DTaP; and studies of the cost-effectiveness of a strategy of
adult vaccination).

ADVERSE REACTIONS

Mild systemic reactions such as fever, drowsiness,
fretfulness, and anorexia may occur after both whole-cell DTP
vaccination and DTaP vaccination. However, data concerning
adverse reactions following the first four doses indicate that
mild reactions are less common among children who receive DTaP.
These reactions are self-limited and can be managed safely with
symptomatic treatment.@@

Moderate-to-severe systemic events (e.g., temperature of
greater than or equal to 105 F {greater than or equal to 40.5 C};
febrile seizures; persistent, crying lasting greater than or
equal to 3 hours; and hypotonic hyporesponsive episodes) have
been reported rarely after administration of DTaP, and occur less
frequently among children administered DTaP than among children
administered whole-cell DTP.

Data from the Vaccine Adverse Event Reporting System
(VAERS)@@@ were used to compare rates of fever, seizures, and
hospitalizations among children who, having had greater than or
equal to 3 previous doses of whole-cell DTP, were administered
either DTaP or whole-cell DTP vaccines for the fourth or fifth
doses (46). During 1991-1993, approximately 5 million doses of
DTaP (distributed by Connaught Laboratories, Inc., or
Wyeth-Lederle Vaccines and Pediatrics) and 27 million doses of
whole-cell DTP were distributed for use among children aged 15
months-6 years. Adverse events were reported significantly less
commonly among the children who received DTaP. VAERS is a passive
surveillance system and these data should be interpreted with
caution because the events reported may be linked to vaccine
administration only by temporal coincidence.

CONTRAINDICATIONS

If either of the following events occurs after

administration of DTaP or whole-cell DTP, subsequent vaccination
with DTaP or whole-cell DTP is contraindicated:

An immediate anaphylactic reaction. Further vaccination with
any of the three components of DTaP or whole-cell DTP should be
deferred because of uncertainty as to which component of the
vaccine might be responsible. Because of the importance of
tetanus vaccination, persons who experience anaphylactic
reactions may be referred to an allergist for evaluation and (if
specific allergy can be demonstrated) desensitized to tetanus
toxoid.

Encephalopathy not attributable to another identifiable cause
(e.g., an acute, severe central nervous system disorder occurring
within 7 days after vaccination and generally consisting of major
alterations in consciousness, unresponsiveness, or generalized or
focal seizures that persist more than a few hours, without
recovery within 24 hours.) In such cases, DT vaccine should be
administered for the remaining doses in the vaccination schedule
to ensure protection against diphtheria and tetanus.

PRECAUTIONS

If any of the following events occurs within the specified
period after administration of either whole-cell DTP or DTaP,
vaccine providers and parents should evaluate the risks and
benefits of administering subsequent doses of a
pertussis-containing vaccine:

Temperature of greater than or equal to 105 F (greater than or
equal to 40.5 C) within 48 hours, not attributable to another
identifiable cause.

Collapse or shock-like state (hypotonic hyporesponsive episode)
within 48 hours.

In circumstances in which the benefits of further pertussis
vaccination outweigh the possible risks (e.g., during an outbreak
of pertussis), DTaP should be administered for the subsequent
doses.

REPORTING OF ADVERSE EVENTS AFTER VACCINATION

As with any newly licensed vaccine, surveillance for rare
adverse events potentially associated with administration of DTaP
is important for assessing its safety in large-scale use. The
National Childhood Vaccine Injury Act of 1986 requires
health-care providers to report serious adverse events that
follow pertussis vaccination (47). The events that must be
reported are detailed in the Reportable Events Table within this
Act, and include anaphylaxis or anaphylactic shock,
encephalopathy (or encephalitis), shock collapse or hypotonic
hyporesponsive collapse, and any acute complication or sequela
(including death) of these events. Adverse reactions should be
reported to VAERS (48). VAERS reporting forms and information are
available 24 hours a day by calling (800) 822-7967.

VACCINE INJURY COMPENSATION

The National Vaccine Injury Compensation Program,

established by the National Childhood Vaccine Injury Act of 1986,
provides a mechanism through which compensation can be paid on
behalf of a person thought to have been injured or to have died
as a result of receiving a vaccine covered by the program
(49,50).

A Vaccine Injury Compensation Table in the Act lists the
vaccines covered by the program and the injuries, disabilities,
and conditions (including death) for which compensation may be
paid. Development or onset of anaphylaxis or anaphylactic shock
less than or equal to 4 hours or encephalopathy with onset less
than or equal to 72 hours after administration of pertussis
vaccine (or sequelae of these conditions) are potentially
compensable under this law. Persons may be compensated for an
injury listed in the established table or one that can be
demonstrated to result from administration of a listed vaccine.
Additional information about the program is available.@@@@

Bernstein HH, Rothstein EP, Pichichero ME, et al.
Reactogenicity and immunogenicity of a three-component pertussis
vaccine administered as the primary series to 2, 4, and 6 month
old infants in the United States. Vaccine 1995;13:1631-5.

* Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine
Adsorbed, ACEL-IMUNE{Registered}, prepared by Lederle
Laboratories and distributed by Wyeth-Lederle Vaccines and
Pediatrics (Pearl River, New York) was licensed on December 30,
1996 for use in infants. The acellular pertussis vaccine
component is produced by Takeda Chemical Industries, Ltd. (Osaka,
Japan), and is combined with diphtheria and tetanus toxoids
manufactured by Lederle Laboratories.

** Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine
Adsorbed, prepared and distributed as Tripedia{Registered} by
Connaught Laboratories, Inc. (Swiftwater, Pennsylvania), was
licensed July 31, 1996 for use in infants. The acellular
pertussis vaccine component is produced by BIKEN/Tanabe
Corporation (Osaka, Japan), and is combined with diphtheria and
tetanus toxoids manufactured by Connaught Laboratories, Inc.
*** Diphtheria and Tetanus Toxoids and Acellular Pertussis
Vaccine Adsorbed, prepared and distributed as Infanrix TM was
licensed January 29, 1997. The diphtheria and tetanus toxoids are
produced by Chiron Behring GmbH & Co. (Marburg, Germany). The
acellular pertussis component is manufactured by SmithKline
Beecham Biologicals S. A. (Rixenart, Belgium).

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Table 5

TABLE 5. Routine diphtheria, tetanus, and pertussis vaccination schedule for children aged <7 years -- United States, 1997
=================================================================================================================================================
Dose Age Customary age/ interval Product * + &
-------------------------------------------------------------------------------------------------------------------------------------------------
Primary 1 2 months Age >=6 weeks DTaP
Primary 2 4 months 4-8 weeks after first dose @ DTaP
Primary 3 6 months 4-8 weeks after second dose @ DTaP
First Booster 15-18 months ** 6-12 months after third dose @ DTaP ++
Second Booster before entering kindergarten or elementary school (not necessary if DTaP
fourth dose {first booster} is administered after fourth birthday)
Additional booster Every 10 years after last dose Td &&
-------------------------------------------------------------------------------------------------------------------------------------------------
* Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP); diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTP)
is an acceptable alternative to DTaP for any of the five doses.
+ Use diphtheria and tetanus toxoids, adsorbed (DT) if encephalopathy has occurred after administration of a previous dose of
pertussis-containing vaccine. If the child is age 31 year at the time the first dose of DT is administered, a third dose administered 6-12
months after the second dose completes primary vaccination with DT.
& Whenever possible, the same DTaP product should be used for all doses. If the same product is not available, Tripedia, ACEL-IMUNE, and
Infanrix TM can be used interchangeably.
@ Prolonging the interval does not require restarting the series.
** If the interval between the third and fourth doses is 36 months and the child is not likely to return for a visit at the recommended age,
the fourth dose of either DTaP or DTP may be administered as early as age 12 months.
++ TriHIBit TM can be administered as the fourth dose following a primary series with either DTaP or whole-cell DTP and a primary series with
any Haemophilus influenzae type b conjugate vaccine.
&& Tetanus-diphtheria toxoids absorbed (Td) (for adult use).
=================================================================================================================================================

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